Obsessive-compulsive disorder (OCD) and major depression, unipolar type (UD), are common, chronic, highly debilitating psychiatric illnesses that have been of great interest to neuroscience for over a century. They exist separately and co-morbidly. Although biological underpinnings are today acknowledged, the brain dysfunctions that may mediate the symptomatic expression of OCD and UD need further clarification. Our (and other) PET studies measuring regional brain glucose metabolic rates implicate an orbital cortical-striatal-thalamic circuit as a possible mediator of the OCD state, while our (and other) PET work implicates lateral prefrontal cortex and caudate nucleus dysfunction in UD. These findings in human functional neuroanatomy warrant intense follow-up, for understanding the pathophysiology of OCD and UD may lead both to new treatment development strategies, and fundamental clues as to how brain mediates complex behavior. This is what motivates this proposal for experiments to further clarify UD and OCD's brain mediation. This proposal's general specific aim is to provide a firm understanding of the different, neuroanatomically organized systems that mediate these two forms of psycho-pathology. Human, rat, and lizard studies that employ PET and autoradiography, along with drug and behavioral manipulations, will be employed to rigorously test specific hypotheses that follow directly from the different cortico-striato-thalamic brain system models of OCD and UD symptom mediation we have proposed. This work is structured as three interactive experiments: l) PET-revealed glucose metabolic rates in UD vs. OCD patients studied pre- and post-treatment with a single agent, paroxetine hydrochloride. 2) Inferior vs. dorsal prefrontal cortex electrical stimulation effects on regional glucose metabolism and behavior in rats; 3) Deoxyglucose autoradiographic studies of cortico-striato- thalamic circuit mediation of social aggressive rituals, and their context-specific behavioral extinction and drug-induced attenuation, in Anolis carolinensis. This work continues and is a logical extension of work on brain systems that may mediate the symptomatic expression of UD and OCD done in this laboratory with NIMH support for l2 years.